PROJECT SUMMARY Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease which is particularly difficult to diagnose because of highly diverse clinical manifestations. Current diagnosis is based on clinical history, physical exam and laboratory studies including serological markers. Despite much effort, the development of improved diagnostic approaches is still in its infancy and has yet to have a clinical impact. Therefore, there is a substantial unmet clinical need for an investment in improving the diagnostic arsenal, particularly approaches that would lead to enhanced diagnostic accuracy of SLE, differentiation of SLE from other autoimmune classes and would provide information concerning disease activity and pathobiology for development of targeted and personalized therapies. We have recently demonstrated the use of differential scanning calorimetry (DSC) as a new diagnostic approach for the analysis of blood plasma samples for the characterization of human diseases. Our data has shown that changes in thermodynamic properties of the high abundance plasma proteome detected by DSC correlate with disease status and therapeutic response in a number of disease settings, including cervical cancer, lung cancer, melanoma, amyotrophic lateral sclerosis, type 1 diabetes, Lyme disease and SLE. We have collected preliminary data on SLE patient samples that have revealed significant differences in thermograms between SLE patients and controls. Comparison of results using DSC profiles (or thermograms) to standard clinical antibody tests revealed significant improvements in sensitivity and overall accuracy with the inclusion of thermogram data. The long term goal of this proposal is to address a critical barrier to early diagnosis thus facilitating effective treatment of SLE patients by developing thermograms as a diagnostic technology. To this end, we will determine the sensitivity of thermograms to multiple SLE clinical and serological factors, disease severity and activity, as well as determine the ability of thermograms to distinguish SLE from other autoimmune and related comorbidities. In addition, we will determine the correlation of thermograms to changes in disease activity, organ involvement and therapeutic intervention during the longitudinal assessment of SLE patients. Finally, we will apply mass spectrometry approaches to interrogate the proteome of SLE patient plasma samples to dissect the biochemical mechanisms by which thermogram modulation occurs in SLE to reveal new biologic information for diagnostic application in SLE. The data gained from this proposal will determine the utility of thermograms for enhanced diagnostic assessment and monitoring of SLE patients and, additionally, could identify new biomarkers associated with SLE pathobiology which could improve our understanding of the disease process and lead to the development of more specific diagnostic tests.